Category: research

We are writing summaries of research papers.

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Untangling the mystery of shape-morphing worm swarms

Original paper: Ultrafast reversible self-assembly of living tangled matter

Author: Sri Ganesh Subramanian
Editors: Jack Llewellyn, Manikuntala Mukhopadhyay

Many of us would have tied several knots very easily, but we all remember the frustration when trying to untangle the cords of a headphone – an experience that often tests our patience. Now imagine a creature that not only creates a tangled ball out of itself and its companions in minutes but can also untangle the entire knot in milliseconds if it senses danger. Meet the California blackworm (Lumbriculus variegatus), a small yet remarkable organism that is teaching researchers innovative lessons about managing tangles (see Figure 1).

Figure 1: (a) A compact, ball-like structure formed by California blackworms (Lumbriculus variegatus), demonstrating their natural tangling behavior. (b) The same blackworms rapidly untangle and disperse in response to a perceived threat. Scale bar: 3 mm.

At first glance, studying the movement of worms might seem unusual or even unpleasant. However, researchers in the Bhamla Lab at Georgia Institute of Technology and Massachusetts Institute of Technology, USA, were captivated by the rapid untangling behavior of these worms. The scientists noticed that these worms naturally tangle together for survival. By assembling themselves in the shape of a compact ball, they reduce water loss, regulate temperature, and protect themselves from environmental challenges. Their most astonishing trait, however, is their ability to instantly untangle (within a few milliseconds) and scatter in random directions when they feel threatened. Scientists are studying these worms to uncover how their movements enable them to form and break apart tangles so efficiently, and how these principles can be applied to develop innovative materials and technologies.

To understand how blackworms form and break tangles, scientists used ultrasound imaging to look inside these clusters. Because blackworms untangle almost instantly when disturbed, the researchers needed a method to slow their movements without harming them. The scientists carefully submerged the worms in a glycerol bath (a non-toxic viscous liquid commonly used in products like chewing gums and marshmallows) at a controlled temperature, to reduce their speed (Figure 2a). After allowing the worms to settle in the glycerol bath, the researchers carefully directed ultrasound waves from multiple directions to track the position of these worms as they moved over one another. This allowed the researchers to create a 3D image of the worms in their tangled state (Figure 2b). What they found was surprising: the tangles aren’t random. The worms were tightly packed, and most of them were in contact with one another, forming an intricate and highly organized structure.

Figure 2: (a) Ultrasound image of a tangled ball consisting of 12 California blackworms immersed in a glycerol bath. (b) Three-dimensional reconstruction of the ultrasound data, showing the positions of individual worms and their interactions within the tangle. Scale bar: 5 mm

By analyzing how the worms moved and interacted, researchers identified specific patterns that dictate how these tangles form and function. They discovered that each worm’s position and movement contribute to the overall structure. Additionally, the size of the tangle could range from a handful of worms to several hundred, depending on environmental conditions and the size of the group. The researchers also discovered that the movements of the worms are critical to their tangling abilities. To tangle, the worms moved slowly and created loops that naturally intertwine. Over time, these loops formed a dense and stable structure. Untangling, however, is a completely different process. When blackworms sense danger, they generate rapid, wave-like motions through their bodies known as helical waves. These waves act like a zipper being undone, loosening the knots and allowing the worms to quickly break free, within a few milliseconds.

To better understand these motions, researchers created mathematical models to understand how the movement of the worms lead to tangling and untangling. The models showed that factors such as speed, direction, and frequency of the worms’ movements are precisely tuned to achieve their goals with remarkable efficiency. One of the most exciting outcomes of this research is the creation of a “tangle map” (see Figure 3). This map identifies the factors that influence whether worms tangle or untangle. These factors include movement speed, the angles at which the worms twist, and how often they change direction. By manipulating these variables, the worms can control whether they form a strong tangle or quickly break free and disperse.

Figure 3: (a) Data generated from ultrasound images show how groups of California blackworms tightly pack together. (b) Scientists used a method called the “diffusion maps algorithm” to trace smooth curves through the worm positions in the ultrasound images, making it easier to track each worm. (c) Tangle graphs were created from these ultrasound datasets to show how the worms are connected and tangled. Scale bars represent 2 mm.

This map also helps scientists understand how to replicate these behaviors in synthetic materials. For instance, by mimicking the worms’ twisting and untwisting motions, engineers could design materials that assemble and disassemble in response to environmental factors, such as temperature changes or mechanical stress. For example, in disaster response scenarios, robots inspired by blackworms could navigate through rubble by tangling and untangling themselves to squeeze into tight spaces. Similarly, materials that adapt to different conditions could improve everything from clothing to architecture. Blackworms remind us that sometimes the solutions to our most complex challenges are hidden in the simplest of creatures.

Disclosure: The author declares no competing interest.

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The Cell with the Dragon Tattoo?

Original paper: Toward Single Cell Tattoos: Biotransfer Printing of Lithographic Gold Nanopatterns on Live Cells

Content review: Merin Joseph
Style review: Arthur Michaut

Introducing the tattoo your boss won’t see, researchers at Johns Hopkins University have developed a “cell tattooing” system that can be used to print patterns onto individual cells. And if that wasn’t enough, it’s gold! The work might not turn out to be the next big thing in fashion, but may allow us to track the health of individual cells as an early indicator of organ-level diseases.

The development of biocompatible electronics has already led to medical technologies including pacemakers to treat heart disease, neural stimulators to treat epilepsy, and even bionic eyes to treat vision loss. But biological devices that can use recent advances in microelectronics to progress further into the realm of sci-fi have been stuck at a roadblock of compatibility. The conditions needed to interface electronics at the scales of individual cells are often lethal to the surrounding tissue.

In today’s post we follow researchers at Johns Hopkins University, who found a creative solution to this biocompatibility problem. Rather than attempting to bind microelectronics to live cells, the researchers coated a gold array with materials that encourage cells to bind to it themselves. The gold provides substance as well as style; it allows for electronics, for example sensors or maybe even remote controls, to be connected with high conductivity and minimal distortion or signal loss. In their paper “Toward Single Cell Tattoos: Biotransfer Printing of Lithographic Gold Nanopatterns on Live Cells”, the team used a technique called nanoimprint lithography to first print patterns of gold, just 250-300 nanometres wide, onto a sheet of glass (i). The patterns were coated to facilitate binding to an overlaid gel (ii), which was then peeled and flipped into a cell culture dish (iii). A gelatin coating was used to encourage cells to stick to the gold-patterned surface (iv). Finally, the setup was flipped onto a new surface (v) and the gel degraded, leaving cells “tattooed” with the gold pattern (vi).

Figure 1: The method used to transfer gold arrays to sheets of live cells.

In a breakthrough for the field, the team found that the setup is non-lethal, and cells retain the gold pattern at their surface. The researchers went further and showed the method can also be used to interface whole organs by attaching a pattern of gold nanowires to a rat brain.

The method used to transfer gold arrays to whole organs. (i) First, nanoimprint lithography is used to array a gold pattern onto glass. (ii) Next, the pattern is coated to facilitate binding to an overlaid gel. Then the gel is peeled off, retaining the gold pattern. As with the live-cell setup, the surface is coated to encourage binding. (iii) The gel-bound gold pattern is then placed onto a dissected rat brain. (iv) Finally, the gel degraded, leaving the organ “tattooed” with the gold pattern.

The researchers speculate that their development of a relatively simple and low-cost biointerfacing method paves the way for more complex devices to be developed that can track, study, and even control individual cells and organs. Maybe soon, all that glitters really will be gold.

Disclosure: The author declares no competing interest.

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“Spleen-on-a-chip” gives an inside view of sickle cell disease

Original paper: Microfluidic study of retention and elimination of abnormal red blood cells by human spleen with implications for sickle cell disease 

Content review: Arthur Michaut
Style review: Arthur Michaut

Though they may not realise it, anyone who’s taken the subway at rush hour knows how a red blood cell feels passing through the human spleen. Almost home now, just need to get through the gates; but wait, someone’s ticket isn’t working, the crowd is starting to push, the gates are getting jammed… Maybe you should have called a cab.

Figure 1. Left: in vivo filtration of red blood cells through the slits of the spleen. Right: in vitro filtration of red blood cells through silicone slits.

Much like turnstiles validating your ticket, the human spleen contains narrow slits that red blood cells must squeeze through to prove they are fit to navigate tight blood vessels while carrying oxygen around the body. The spleen is tasked with ensuring our blood contains the right amount of red blood cells and removing any cells that aren’t in tip-top shape. Shape, however, can be a problem the spleen can’t handle.

People with sickle cell disease produce “sickle” shaped red blood cells due to an inherited genetic mutation. Sickle cell disease patients can experience episodes of acute splenic sequestration, or “spleen crisis” where these misshapen cells clog the slits of the spleen, depriving it of oxygen and leading to swelling that can become life-threatening. Because this process is difficult to observe and monitor in the body, there is little understanding of how and why a spleen crisis might occur. When a spleen crisis occurs, an urgent blood transfusion is needed to treat the problem, however, in some cases, it becomes necessary to surgically remove the spleen.

A group of scientists spanning the USA, France, and Singapore have teamed up to understand how sickle cell disease can become life-threatening. Their device, a silicone model spleen, could be used to predict complications of the disease as well as develop new treatments.

Using a soft material classically used in microfabrication, named PDMS, to cast a mold with slits similar to those in the human spleen (Figures 1 & 2i), researchers were able to directly observe the processes that lead to spleen crises. The group analysed flows of red blood cells from both healthy and sickle cell disease patients through the silicone spleen, simulating splenic blood flow rate and oxygen levels, and measured retention of cells in the slits of the device.

The flow of red blood cells from healthy and sickle cell disease patients through the silicone spleen.
Figure 2. (i) The biomimetic “spleen-on-a-chip”, scale bar 10 µm (with higher magnifications outlined in red, right). The majority of red blood cells from healthy patients (ii) pass through the device, however, cells from sickle cell disease patients (iii) are more frequently retained at the slits of the device, and when deprived of oxygen (iv) these cells block the device entirely.

After one minute of blood flow, red blood cells from sickle cell disease patients blocked more than double the number of slits as healthy red blood cells (Figures 3i & 3ii), demonstrating how the spleen can become blocked and swollen in sickle cell disease patients. When the silicone spleen was deprived of oxygen, as occurs during a spleen crisis, red blood cells from sickle cell disease patients became stiffer, more viscous, and more frequently sickled (Figure 3iii). Under this condition, sickled red blood cells completely blocked all of the slits. Upon reintroducing oxygen into the system, many cells return to their normal shape and blockages begin to open up again within seconds (Figures 3iv & 4).

(i)
(ii)
(iii)
(iv)
Figure 3. (i) Filtration of red blood cells from a healthy patient through the silicone device. (ii) Sickled red blood cells from sickle cell disease patients are stiffer and more viscous, making them more likely to get trapped in the slits of the device. (iii) When deprived of oxygen, simulating a splenic crisis, red blood cells from sickle cell disease patients become stiffer and are more prone to sickling, causing a complete blockage in the device. (iv) Reintroducing oxygen into the device clears blockages of sickled cells. The researchers believe this mimics the effects of a blood transfusion to alleviate splenic crisis.
The effects of de- and re-oxygenation on red blood cells from healthy and sickle cell disease patients and the unblocking of the device following reoxygenation.
Figure 4. Left: red blood cells from healthy (AA) and sickle cell disease (SS) patients under oxygenation and deoxygenation conditions (scale bar 10 µm). Right: the percentage of open slits in the device quickly increases when oxygen is reintroduced into the blocked system.

The results uncover a viscous cycle leading to spleen crises in sickle cell disease patients. Sickled cells cause blockages in the spleen, which deprives the spleen of oxygen, which in turn causes more cells to become sickled. Additionally, it was shown that the addition of oxygen caused cells to “unsickle” and rapidly cleared blockages in the slits, revealing why immediate blood transfusion can alleviate spleen crises. The researchers speculate that a sudden burst of oxygen-rich red blood cells via transfusion has the same effect as when they reintroduced oxygen to their blocked system.

Researchers believe the spleen-on-a-chip could become a new tool to allow sickle cell disease patients to monitor their condition and allow for early diagnosis of spleen crises, as well as providing a testing ground for new treatments against the disease. Safe travels red blood cells!

Disclosure:  The author declares no competing interest.

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Bioinspired e-skins: camouflaging with the flip of a switch

Original paper: Bioinspired MXene-Based User Interactive Electronic Skin for Digital and Visual Dual Channel Sensing   

Content review: Heather Hamilton
Style review: Arthur Michaut

Human skin has many functions beyond ensuring that all of our insides stay, well, inside. Skin also acts as a giant sensor that feels sensations like pressure, temperature, or vibration, and converts them into electrical signals to be processed by the brain. In the animal kingdom, some species like chameleons can even use their skin to selectively blend into their environments. Scientists have set out to create electronic skins, or e-skins, that can mimic or even outperform the typical functions of the human skin by taking on color-changing abilities like chameleon skin. Polymer materials are excellent for mimicking skin due to their soft and elastic nature that allows them to bend and stretch without tearing. However, most polymers are not conductive, a necessary property for transporting electrical signals. To create e-skin, conductive materials are often integrated into polymer materials to add electronic properties to a flexible skin-like matrix. By also integrating a color-changing pigment, researchers from Tongji University created a unique e-skin that could digitally via measurement of current flow and visibly detect mechanical movements and change color for effective camouflaging. 

Conductive, metal-based nanosheets, called MXenes, were used because of their hydrophilic quality, which means they like water similar to our skin cells. When encapsulated in the polymer matrix, the nanosheets are connected and can conduct electrical current. However, when the e-skin stretches, the nanosheets become disconnected and stop conducting the current. To remedy this, smaller conductive materials called carbon nanotubes were mixed with cellulose nanofibers and added to the e-skin. The cellulose nanofibers (CNF) help disperse the carbon nanotubes (CNT) similar to how coating fruit with flour before adding to cake batter helps the fruit disperse in the cake during baking rather than sinking to the bottom. The carbon nanotubes act as a bridge between nanosheets in stretched states as seen in Figure 1.

Figure 1. Schematic of conductive e-skin components in response to stretching.

The researchers measured the resistance to electrical current flow, or resistivity, to determine the e-skin electrical response to stretching. The difference in electrical current between an unstretched and stretched e-skin can be used to detect large movements, like a finger bending at different angles, and subtle movements, like throat movements while swallowing. As shown in Figure 2, the e-skin exhibits different relative resistance to the flow of the current at different finger bending angles. 

Figure 2. Signal responses in the form of relative electrical resistance, (R-R0)/R0, showing mechanical movements can be detected by e-skin.

From their experiments, the researchers realized that the e-skin may have Joule heating capabilities meaning the e-skin would heat it up when current is flowing through it and quickly cool down as soon as the current is turned off. Inspired by color-changing abilities found in some animal skins, the researchers also mixed thermochromic pigment into the polymer matrix before casting the e-skin. These pigments change color as they are heated above 31°C. (Figure 3a).

Figure 3. E-skin containing thermochromic pigment in response to (a) Joule heating and (b) stretching.

As soon as the current is turned off, the e-skin begins to cool, returning back to its initial color. Since the current flow can be altered by stretching the e-skin, the temperature and subsequent color can also be changed by stretching the skin. When current is flowing through the unstretched skin, the e-skin temperature increases, causing it to turn white. When stretched, an increase in electrical resistance causes the e-skin to return to its initial color. Instead of waiting for an electrical current reading, strain and temperature are visibly detected by the color of the e-skin. This strain color-changing ability was used to detect finger movements when the e-skin was applied on a hand (Figure 3b). To demonstrate the camouflage phenomenon similar to a chameleon changing its colors to mimic the environment, an e-skin was attached to a green plant (Video).

Video. E-skin changing color to match the color of the green plant.

The e-skin changes color from a dark green to a light green similar to the plant in about 90 seconds simply by turning on a current. This e-skin camouflaging ability goes well beyond the natural abilities of human skin and would be useful for military applications for quick camouflaging. The creation of this multifunctional e-skin is an exciting innovation for the wearable technology field and brings us one step closer to becoming chameleons.

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Trichoplax adhaerens: tropical sea-dweller, microscopic contortionist, and biomechanical marvel

Original paper: Motility-induced fracture reveals a ductile-to-brittle crossover in a simple animal’s epithelia

Content review: Heather Hamilton
Style review: Pierre Lehéricey

Figure 1: The dynamic range of T. adhaerens with size ranging from 100 microns to 10 millimeters. Snapshots taken from live imaging. Images courtesy of the original article.

Meet Trichoplax adhaerens, a microscopic marine animal from one of the oldest known branches of the evolutionary tree. It looks like a microscopic cell sandwich: two layers of epithelial cells (which make up the surfaces of our organs), with a layer of fibre cells in between. As depicted in Figure 1, T. adhaerens takes a wide variety of shapes from disks to loops to noodles and more. Oddly,  T. adhaerens ruptures when it moves around, a self-induced fracture behavior that has recently captured the attention of physicists and engineers. Fracture is the technical term describing the process by which an object breaks into distinct pieces due to stress. These animals push their epithelial tissue to the breaking point, forming incredible and extreme shapes before separating altogether. This is a surprising behavior for epithelia, which usually prefer to maintain their integrity.  By modeling how T. adhaerens rips itself apart when moving, we can improve our understanding of how soft materials and especially biological tissues behave on the verge of breaking.

Prakash, Bull, and Prakash conducted a two-pronged analysis of fracture in T. adhaerens:  live imaging to record the fracturing in real time and computational modeling to simulate the response of the tissue when stretched too far. The drastic mechanical behavior in question also motivated the researchers to perform a more general inquiry into the competition between flow and fracture in materials that are dramatically deformed relatively quickly. Flow is like stretching out a piece of chewing gum, whereas fracture is like snapping the gum in two. The computational model proposed by the authors helped paint a clearer picture of what happens when T. adhaerens rips apart.

Figure 2: Model tissue is described as a collection of balls and springs. Balls represent cells, and springs represent the sticky adhesion between cells. Springs apply restorative forces to the cells, but can break if stretched too far. This model was used to study the ventral (bottom) epithelial layer, which consists of epithelial cells (green) and larger lipophil cells (red). Figure courtesy of the original article (Extended Data).

The computational model that the researchers used is based on a sticky ball and spring model, as shown in Figure 2, where each ball represents a cell and each spring represents the sticky junctions that cells use to adhere to one another.  The springs break if the balls move too far away from each other, which represents cells being unstuck from their neighbors.  Two cell types are represented in the model epithelial layer in Figure 2: epithelial cells, which are small and comprise the bulk of the tissue, and lipophil cells, which are larger and less common.  Using this model for living tissue, the authors conducted computational simulations where the tissue was stretched to a breaking point. They found that there are three possible tissue behaviors that depend on the strength of the driving force applied to the simulated tissue. For weak forcing (low stress), the tissue behaved elastically and so responded in such a way that it could recover its original shape. For intermediate forcing (medium stress), the tissue underwent a “yielding transition” where the material transitioned from elastic response to plastic response. During plastic response, permanent distortions occurred in the material, and the material could not recover its original shape. In this case, the tissue is ductile and undergoes local changes, like cells interchanging with neighboring cells, to relax some of the pent-up stress. For stronger forcing (high stress), the tissue undergoes brittle fracture where the bonds between cells break with little opportunity for relaxation. The three behaviors in the model represent a transition from elastic to ductile to brittle responses. Using this model of tissue response to applied force, the authors mapped the conditions that lead to different tissue behaviors, as sketched in Figure 3.

Figure 3: Tissue phase diagram (elastic-ductile-brittle) generated by the tissue simulations. The elastic regime (i) implies that bonds do not break, and neighbors are not exchanged. Above the yield transition (blue line), cells undergo local relaxations and flow in the ductile yielding regime. To the left of the red line, cell bonds tend to break and form gaps between cells, demarcating the brittle fracture regime.  Figure courtesy of the original article.

Guided by a better understanding of tissue mechanics thanks to the computer model, the authors experimentally measured the brittle and ductile responses in T. adhaerens. They found that both material responses can occur in our microscopic friend. The ability to access both regimes is important because the ductile response yields by flowing (helping form the longer shapes in T. adhaerens) whereas the fracture response accounts for asexual reproduction by splitting into two separate new individuals. The authors’ combined approach of experimental data that motivated the development of a computer model, which in turn guided further experimental inquiry, is an important modern scientific paradigm. Both approaches are incredibly important tools in the biological and soft matter sciences’ toolkit. Joint application of these tools lets us draw general conclusions from specific experiments as well as apply those general conclusions back to answer specific questions – like explaining how T. adhaerens achieves the diversity of shapes in Figure 1 and how this relates to its hardiness and evolutionary goal of reproduction.  Further, the epithelial layer computational modeling technique generalizes this tissue mechanics study to help us describe fracture versus flow in any living tissue, including our own.

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Don’t French kiss the frog prince : how to make better adhesives by mimicking the frog tongue and saliva

Original paper: Frogs use a viscoelastic tongue and non-Newtonian saliva to catch prey

Content review: Olga Shishkov
Style review: Heather S. C. Hamilton

What do a frog’s tongue and a piece of Scotch tape have in common? Not much at first glance. However, if you press your finger on either one of them, you will certainly feel a sensation of stickiness. Taking a closer look at the schematic in Figure 1, you will realize that these materials have a similar structure, simply a layer of glue on a substrate. For the sticky tape, the substrate is a plastic strip and the glue is made of polymers and additives which increase the stickiness of the glue. For the frog tongue, the substrate is the tongue and the glue is the saliva.

Figure 1. Schematics highlighting the structural resemblances between Scotch tape and frog tongue, both composed of a substrate on which a glue lays on

These two adhesives work quite in the same way. Let’s have a look at your classic sticky tape: when you press some scotch tape on a wall to hang your favorite poster, the glue will flow and wet all the crevasses of the wall and the poster. This process is not instantaneous though. Indeed, in order to have an efficient wetting of the surface, you have to press on your Scotch tape for several seconds, and maybe press several times. Eventually, this will generate many anchoring points between the glue and the texture of the surface. When you stop applying pressure to the tape, the glue does not flow any more, it becomes stiffer and remains adhered to your wall. However, when you peel the scotch tape, or when the object you taped is too heavy, stress is reapplied to the tape adhesive as illustrated in Figure 2. These forces will make the glue flow, the anchor points will fail, and the adhesive will be removed from the wall. No chemical bonding is involved in these adhesives: only applied stress, or the lack thereof, makes the glue flowable or not, which is why these adhesives are called pressure-sensitive. The longer you press on your sticky tape, the better the final adhesion will be as you will increase the time for the glue to flow into every detail of the surface you would like to stick your tape to.

 Figure 2. Principle of a pressure-sensitive adhesive : (a) Application of the adhesive by fluidizing the glue due to the pressure applied on the tape, thus wetting the wall. (b) Removal of the adhesive by fluidizing the glue due to the force applied on the glue by peeling the tape   

But a frog catches insects or bigger animals such as snails or slugs on its tongue in less time than the blink of an eye (under 0.07 seconds), way faster than applying your Scotch tape to a wall. A team of researchers from Georgia Tech tried to understand how a frog’s tongue can achieve this feature, because understanding the biomechanics involved can inspire synthetic high-performance adhesives with fast application times. Alexis Noel and colleagues first measured just how powerful a frog’s tongue strike is by taking a high-speed video of a leopard frog, Rana pipiens, capturing an insect. They discovered that the captured insect can feel a force equal to up to 12 times its own weight when the tongue impacts it. To find out how the frog uses these high forces to stick the insect to its tongue, Noel and colleagues characterized the saliva and the tongue separately. 

By testing the mechanical response of the saliva under deformation in an instrument called a  rheometer, researchers showed that the saliva was shear-thinning. This means that when a small rate of deformation is applied, the saliva is very viscous, 50,000 times more viscous than human saliva. However, at high rates of deformation, the viscosity of the saliva decreases significantly causing it to flow like a fluid. When the frog strikes an insect with its tongue, the shock from the impact deforms the saliva making it less viscous so it flows easily and coats the insect as shown in Figure 3. After the initial deformation caused by the impact, the viscosity of the saliva increases and the insect is trapped in a very thick fluid.

Figure 3. (a) to (c): Three-step mechanism of prey capture of an insect by a frog. The tongue stretches (a) until it impacts and wraps around the insect, covering it with saliva (b). The insect is glued to the tongue which retracts into the mouth of the frog (c). Details of the saliva coating of the insect are shown in (e) before the impact of the tongue when the saliva stands at rest and in (f) after the impact when the saliva has lower viscosity and spreads on the insect. Courtesy of the original article.

By poking the tongues of six different frogs and two different toads with a metal cylinder, a test called indentation, the researchers measured the ratio between the applied force on the tongue and its resulting deformation. This ratio, called Young’s modulus, describes the softness of the tongue. On average, the frog tongues have Young’s modulus ten times lower than that of a human tongue, making them ten times softer than a human tongue. Frog tongues are able to deform around the insect to increase the prey-tongue contact surface area. Soft frog tongues also absorb the massive shock from impacting an insect much like a car’s shock absorber. The internal damping of the soft tissue allows the tongue to wrap around the insect during the capture and keep it in contact with the prey for good adhesion with the saliva. Now that the insect is trapped, how does the frog bring back its prey to its mouth?  It is crucial to keep the insect coated in the sticky saliva as the tongue is retracted back into the mouth of the frog because this happens as fast as the initial stretching for insect capture. Remember the sticky tape example? Applying too much stress on the glue by peeling off the tape makes the glue flow, resulting in a loss of adhesion. The soft tongue dampens the stress of retraction on the saliva to prevent it from flowing. Once the insect is in the frog’s mouth, the only way to release the prey from its tongue and eat the insect is to retract its eyeballs, thereby squeezing the tongue hard enough so the saliva can flow again and free the prey.  

Overall, this mechanism using a soft tongue and shear-thinning saliva shows great adhesive performances at speeds unmatched with synthetic materials. This article shows once again that nature can produce amazing materials and concepts which could be used for bio-inspired designs of synthetic analogs. Thanks to the deeper understanding of the frog prey-catching phenomenon, one can of course think about more efficient pressure-sensitive adhesives or glue guns, but also about robots trained to catch dangerous insects as fast as a real frog. 

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Totally tubular: Polymer plumbing for tissue engineering

Photos of polymer hydrogel tube tied in a knot and stretched by a researcher wearing purple gloves.

Original paper: Multilayer Tubes that Constrict, Dilate, and Curl in Response to Stimuli

Content review: Danny Seara
Style review: Arthur Michaut

Our bodies rely on many types of tube-shaped organs to transport blood, air, water, food, urine, and feces. These tubular organs are stimuli-responsive: they can constrict or dilate, secrete chemicals, or act as a selective barrier in response to biological signals. Developing synthetic versions of natural tissue structures that mimic biological responses is at the cutting edge of tissue engineering, synthetic organ development, and even soft robotics design. But what materials can be used to grow responsive tubes in the lab? Many of the fundamental building blocks of biological tissues are naturally occurring polymers. However, growing stimuli-responsive tissue mimics with these materials has not been achieved. Fortunately, many examples of biological tissue have similar properties to synthetic polymer hydrogels which are easy to make in the lab. Polymer hydrogels are made of interconnected networks of synthetic polymer chains, linked together by crosslinker molecules and swollen with water – kind of like a wet sponge as shown in Figure 1. However, many processes that are currently used to make tubes from hydrogels require specialized equipment, like coaxial printing which requires many different custom-made print heads to make different sized tubes. In addition, such techniques don’t easily produce branched tubes common in biological systems. Recently, a group of engineers designed a simple and elegant method to construct stimuli-responsive millimeter-scale biomimetic tubes using a simple patterning process.

Colorful cartoon schematic showing the stepwise process of polymerization from iniator, monomer, and crosslinker small molecule to crosslinked polymer chains to hydrogel materials.
Figure 1. Synthetic crosslinked polymer are made by combining initiator, monomer, and crosslinker molecules (a) and initiating a polymerization reaction (b). This results in the formation of polymer chains that are crosslinked by covalent bonds (c) to form very large network molecules (d). When these networks swell in water, they form hydrogels (e). Hydrogels can be engineered to have similar water-to-organic content and mechanical properties as biological tissue.

To make tube-like structures, the researchers first mold a cylindrical template using the biopolymer agar (a natural vegetable gelatin) and then infuse it with initiator molecules. To grow a polymer hydrogel around the template, the agar cylinder is suspended in a bath containing monomer and crosslinker molecules. Once activated, the initiator molecules can leak out and interact with the monomers and crosslinkers in the bath to polymerize a hydrogel sleeve around the template. The researchers also added xanthan gum to thicken the monomer bath so the template can be suspended and a structurally sound tube can be grown (no cracks, holes, or missing tube walls). Finally, the agar template is dissolved in hot water, leaving a synthetic hydrogel tube. Figure 2 shows a schematic of this “inside-out” polymerization process.

Colorful cartoon schematic showing the stepwise process to make polymer hydrogel tubes with two photographs showing the finished tubes.
Figure 2. The simple method to grow synthetic polymer hydrogel tubes around degradable agar templates is represented by this schematic. Scale bars represent 4 mm. Schematic design and images courtesy of the original article.

The researchers were able to fabricate tubes with different geometries and patterns, growing proof-of-concept mimics of naturally occurring biological tube structures. Changing the diameter of the template cylinder controlled the size of the lumen (inner diameter) of the tube. The researchers could vary the lumen by an order of magnitude, from 4.5 millimeters down to 0.6 millimeters. A 20-minute “inside-out” polymerization reaction produced tubes with ~1 millimeter thick tube walls. Increasing the concentration of initiator in the template or the polymerization reaction time produced thicker tube walls. Adding xanthan gum to the monomer bath modified its viscosity and allowed the researchers to spatially separate different monomer species in the bath from left to right or top to bottom. In this way they could create patterned hydrogel tubes, such as tubes with lateral patterns (rings around the tube) and longitudinal patterns (stripes along the tube walls), as shown in Figure 3. By designing different hydrogel tube patterns, the researchers were able to grow synthetic tubes that responded to different stimuli much like biological tubes respond to stimuli in living organisms. 

Colorful cartoon schematic showing the stepwise process to make polymer stimuli-responsive hydrogel tubes using a different stripe patterns.
Figure 3. Shape-changing synthetic hydrogel tubes are made using viscous patterned monomer baths to embed lateral patterns (a) or longitudinal patterns (b). Three types of hydrogels were used to make these patterns: (i) a hydrogel that is non-responsive to temperature- or pH-based stimuli; (ii) a hydrogel that responds to increased temperature by contracting (shrinking in volume); and (iii) a hydrogel that responds to pH change by expanding (growing in volume). Schematic design and images courtesy of the original article.

The researchers used monomers that form responsive polymers to pattern the tubes and achieve different tube responses. The laterally-patterned tubes constricted with temperature changes and dilated in response to chemical triggers, like pH change. The longitudinally-patterned tubes curled into loops with temperature change. These coils formed because the tube components responded differently to changes in temperature (one component expanded more than the other) which caused the tube to bend. The researchers were even able to make rudimentary branched systems where the branches from the main tube could be programmed for different stimuli-response properties. 

A really exciting aspect of this method is that it works at physiological conditions (room temperature, aqueous environments, etc.). This means cells or other bioactive materials can be incorporated during tube-making, which is advantageous for regenerative medicine. This work is a great example of translating the fundamental study of polymers and responsive materials into real world applications. It also suggests many new engineering questions: Can we make synthetic and responsive tube systems from biopolymer hydrogels (like collagen or cellulose)? Can we incorporate synthetic tubes into other soft materials like gels or colloids to make complex structures? Can synthetic tubes be designed as chemical reaction conduits or implantable biological sensors? Can soft robots use tube systems for autonomous motion? The industrious tube engineer might imagine designing a patterned multi-tube system to generate tube-shaped robots that can crawl or grab objects using coiling tube tentacles. Ultimately, this work helps set the trajectory of future research as we head towards our not-so-distant future full of engineered tubular organs and squishy robots.

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Real soft bites made by a model tongue to better assess food texture

Original paper: Compression Test of Food Gels on Artificial Tongue and Its Comparison with Human Test

Content review: Arthur Michaut
Style review: Heather S. C. Hamilton

Food texture, or how soft or hard your food is, is usually assessed with a machine that compresses food between two metallic plates. This instrument oversimplifies what really happens in our mouth, because the stiffness of the metallic parts does not mimic the natural deformability of the tongue. This leads to a strong deviation of the results of these experiments from sensory evaluations of food texture by humans. Practically, this can lead to hard-to-swallow food being considered soft and safe for people with dental or swallowing problems. A team of Japanese scientists tried to tackle that problem by developing a synthetic tongue which would lead to better food texture assessment with a test machine. But what are the important properties that characterize a successful model tongue?

To answer this question, the researchers compressed the tongues of seven brave human subjects using a clamp equipped with a force sensor like the schematic in Figure 1a. The human tongue is considered an elastic material, meaning that it can be deformed (by compression for example) and will return to its original size and shape after the force causing the deformation is removed. Deformation is often measured as percent strain, or the ratio of deformed size to original size of an object. Using this compression technique, which seems a bit medieval, and with the help of the human subjects, the researchers determined how the human tongue responds to an applied strain of up to 20%. Understanding the mechanical properties of the tongue means it can be modeled by an equivalent soft material and tested in a similar manner, as shown in Figure 1b. 

Figure 1: Schematic of the steps to design an in vitro system for tongue-palate compression tests. Tongue elasticity is first measured with a clamp (a). A silicone rubber tongue with a similar elasticity is then put on the bottom plate of a compression test machine to mimic the tongue (b). The metallic top plate will act as the palate, or the hard roof of the mouth.

The synthetic tongue produced for this study was a cylinder made of silicone rubber with an elasticity that is similar to the elasticity of the real tongues of seven human subjects. Remarkably, the tongues of seven subjects were considered a large enough sample size to determine the elasticity of an average human tongue, with resulting measurements close to values reported in the literature. In the food texture assessment device, the top metallic plate is left unaltered to mimic the palate. Pieces of agar gel, a jelly-like material made from seaweed, are used as a test food product. Several agar gel samples were prepared, each requiring some force to fracture, breaking into smaller pieces. Mechanical tests were performed with the in vitro tongue-palate system, while in vivo testing was determined by the same seven subjects who had their tongues clamped in the compression test. The in vivo results determined if the subjects were able to fracture the gel by tongue-palate compression or if they needed to chew the gel. These results were compared to the in vitro observations.  

The most interesting result highlighted by the study, shown in Figure 2, is the threshold above which mastication, the action of chewing with your teeth, was needed to break the agar gel into edible pieces. At a strain of 10%, if the agar gel sample was more deformed than the silicone rubber of the artificial tongue, the agar gel would fracture to the consistency of mashed potatoes. Otherwise, if the silicone rubber was more deformed than the agar gel sample, the gel sample would remain intact, meaning that a force higher than the one provided by tongue-palate compression would be needed for fracture, such as the force provided by mastication. Indeed, during tongue-palate compression, both the tongue and the model food are deformed under the action of reciprocal forces.

Figure 2: Strain profiles of the agar gel and the silicone rubber over time under compression by the tongue-palate model. At 10 % strain, if the agar gel curve is below the silicone rubber curve (a, top), which means that it is less deformed, then it will be more resistant to compression and will not collapse (a, bottom). If the opposite scenario takes place (b, top), then the gel will fail (b, bottom).

This is exactly how the human tongue acts like a mechanical sensor, thanks to the difference of stiffness between the organ’s tissues and the material probed. The resulting feeling will then influence the strategy used by our mouth to break down food in small ingestible (soft)bites. Food with a soft texture will only need this tongue-palate compression to be edible. Alternatively, foods with a tougher texture will need fragmentation through mastication. It is to be noted that the strategy used by the subjects eating the same agar gels matched the results of the in vitro compression tests: if the agar gel collapsed during the test, only tongue-palate compression was needed. 

Therefore, food products that would fracture during this compression test can be considered soft enough to be edible without chewing. Even if this system is not a perfect model since the synthetic tongue does not replicate the complex arrangements of different tissue layers present in the human tongue and a model saliva is not included, it can be of great help to design safe food for people with mastication problems. 

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“I don’t think there will be a return journey, Mr. Frodo”: how thermodynamic irreversibility makes life flourish

Original paper: Statistical Physics of Self-Replication

Content review: Adam Fortais
Style review: Andrew Ton

Understanding the origin of life is one of the most enduring and fundamental scientific challenges there is. Of all branches of science, physics is probably not the first place one would think to go to for enlightenment. Life seems too complicated and multi-layered to be captured by the simplistic frameworks of physics. Today’s paper tackles a small part of understanding the origin of life – the physics of self-replication.

This paper begins by considering two macroscopic states, shown in Figure 1A, which are “one bacterium in a petri dish” and “two bacteria in a petri dish”, and considers transitions between these states. The biggest challenge here is relating a macroscopic change — the replication of a cell or collection of complex molecules — to a set of microscopic operations, also known as chemical reactions.  But these reactions are tremendously complicated. How can we know what to expect from them? The answer lies within the art of thermodynamics. 

Figure 1. Some of the pathways considered in the process of cell division. The probability of cell division (A) occurring is much higher than that of the disintegration of a single cell (B), highlighting the irreversibility of this event. Image courtesy of the original article.

According to thermodynamics, the governing quantities in a typical chemical reaction are energy, heat, and entropy. During a reaction, they can gain or lose any of these three as long as the total energy is kept balanced. Entropy, however, is a bit more special than the other two. Roughly speaking, entropy is a way of counting the number of possible ways a system can be in a certain state. So if a reaction involves several small molecules binding together to form a larger molecule, that involves a big loss in entropy. This is because there are many more ways to organize a large number of molecules than ways to organize one. Thermodynamics tells us that heat must be released to “pay for” this change in entropy. This heat flow increases the entropy of the environment, leading to an overall increase. All other things being equal, systems tend towards states of high entropy, simply because there are more ways of being in those states. This is usually referred to as the Second Law of Thermodynamics.

These are abstract descriptions of thermodynamic processes — how does the author use these to construct more concrete, quantitative models? First, they derive a version of the Second Law which relates the heat released by the transition to the irreversibility of the transition: the harder it is to undo a process, i.e. the more irreversible it is, the more heat must be released. Combining this observation with a simple model of replication, England reaches an important result: for a self-replicating system, the more efficiently it uses the available energy, the more rapidly it will replicate. 

England uses thermodynamics as a set of rules to calculate whether cell division for a bacterium is physically possible. While we already know the answer, the author is seeking to understand if this simple theory contains enough details to make accurate estimates about bacterial replication. The hard part of this problem isn’t to calculate the heat or entropy released, but rather to put a physical constraint on the likelihood of the reverse process. After all, we don’t ever see bacteria spontaneously dissolve back into their constituents. But with some clever thinking, this problem can be circumvented. Instead of considering the probability of a bacterium dissolving, the author simply considers the probability of every single chemical bond inside it spontaneously breaking. This is an extremely unlikely event, and yet it’s not as unlikely as the cell spontaneously being unmade, as shown in Figure 1B, and so it can give us a lower bound for the irreversibility of cell division. Combined with careful estimates of heat and entropy transfers, this gives a full (and very approximate) thermodynamic accounting of the process of cell division.

What can we do with this? We can perform some comparisons: first of all, the irreversibility of a process turns out to be a much larger thermodynamic barrier than the entropic difficulty of organizing all the constituents of a daughter bacterial cell, which is a highly structured object! This is surprising at first, but hindsight is 20/20: living systems are doing a lot of work to make things that don’t dissolve back into water. Another surprising conclusion of this argument is that real bacteria are tremendously efficient! With the coarse estimates used here, the author gets a replication rate close to that of a real E. Coli bacterium. This is an astonishing result, since the process considered here is not nearly as irreversible as that of a real cell division. 

The takeaway here isn’t simply learning something about bacteria or replication. The real lesson is about the power of the methods of statistical physics. The division of a bacterium is frighteningly complicated, and no physicist could write down the chain of reactions necessary for the proper replication and division of this complex system. Despite this intricacy, biological processes must still follow the unambiguous laws of physics. And that implies one thing: more life, more complexity, and more entropy. While this is by no means an answer to the question “where does life come from?”, it gives us hope that physics will continue to play an important role in the story of answering this question.

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Plants detect gravity by going with the (granular) flow

Original paper: Gravisensors in plant cells behave like an active granular liquid

Content review: Adam Fortais
Style review: Heather S.C. Hamilton

Plants need to know the direction of gravitational pull in order to grow their roots downward and their stems upward. This information is crucial whether the plant grows in your garden, on a cliffside, or even on the International Space Station [1]. While it’s been said that it took a falling apple for Newton to figure out how gravity works, our photosynthetic friends use a more intricate microscale sensor to detect gravity. This sensor consists of starchy granules called statoliths which can be found on the bottom of specialized cells called statocytes. An accumulated pile of around 20 statoliths at the bottom of a statocyte cell is shown in Figure 1. If the cells are tilted like in Figure 2, the pull of gravity initiates a statolith avalanche that indicates the direction of gravity. The position of statoliths is part of a complicated signaling network that tells the plants how to correct its growth towards or against the direction of gravitational pull. 

Figure 1. Microscope images of statolith piles in gravity-sensing statocyte cells of wheat coleoptiles, which are the sheaths covering an emerging shoot of wheat. Arrows indicate the direction of gravity. (Left) Statolith piles are visible as dark areas on the bottom of the cells. The scale bar represents 100 µm. (Right) Close-up view of the statolith piles. The scale bar represents 20 µm. Images courtesy of the original article. Inset: Standard granular pile just below the avalanche angle. Schematic courtesy of Andreotti et. al., Granular Media Between Fluid and Solid.
Figure 2. Movie made from microscopic images of statolith avalanches in wheat coleoptiles after the cells are tilted 70 degrees. Statolith piles are dark spots. Movie runs at 40x speed for a total duration of 10 real minutes. Courtesy of the original article.

However, Bérut et. al. realized that this description of statolith piles didn’t totally agree with our knowledge of granular materials. There are two major issues. First, granular piles are known to initiate avalanches only when the slope of the pile reaches a critical angle, usually between 5° and 30° depending on the characteristics of the grains. In the case of the statoliths, the critical angle was found to be around 10°. When the slope is lower than the critical angle, the pile should be completely immobile due to frictional forces between the grains. However, plants are able to detect even the slightest changes in gravity — involving angles much smaller than 10° — indicating that avalanches are not the whole story. Secondly, upon tilting as in Figure 2, the grains seem to avalanche until they establish a flat surface layer. This is in direct contrast to classical granular materials. If statoliths behaved classically, we would expect them to avalanche until the critical angle of 10° is reached, rather than their actual final angle of around 0°. How can we explain the shocking sensitivity of these granular piles?

Figure 3. (A) Two observed dynamical regimes in the averaged angular decay of statolith pile slopes over time. Each curve corresponds to different initial inclination angles. (Inset) Initial and final configurations of a statolith pile after being tilted by 70°.  (B) Close-up video of a statolith avalanche (when tilted 15°)  highlighting the random motion of individual statoliths. Movie is played at 80x speed, for a real duration of 14 minutes. Images and video courtesy of the original article.

By studying the flow response of the statoliths to gentle inclinations, Bérut et. al. found that the statoliths in fact flow, liquid-like, from a pile into a puddle with or without prior avalanches!  Figure 3A shows a statolith pile angle slowly creeping from 10° (or less) to 0° in 10-20 minutes. This creeping response occurs at any slope. Under the microscope, the statoliths are seen to vibrate, with each individual statolith undergoing random motion shown in Figure 3B. The statoliths are agitated, the origin of which is likely biological processes within the cell rather than random thermal motion, as thermal energy is too small to drive the observed grain activity. While we know that classical granular piles do not flow below the critical avalanche angle, this is not the case for active granular materials. Agitation allows the grains to free themselves from the pile, turning an otherwise static mountain into a fluid-like substance. Long before we had an understanding of the physical world, nature was already building and refining amazing biological machines. We have only recently begun to understand the properties of agitated granular materials, meanwhile plants have been using active grains to detect gravity all this time. Given plants’ long-time expertise with gravity, perhaps the apple that fell on Newton’s head was nature’s way of telling humans to hurry up and figure it out. 

 [1] NASA Plant Gravity Perception Project